The article discusses the concept of functional selectivity in pharmacology, challenging the traditional definition of intrinsic efficacy. Recent data have shown that ligands can differentially activate signaling pathways mediated by a single G protein-coupled receptor (GPCR), leading to phenomena such as agonist-directed trafficking and biased agonism. The authors present examples from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems to illustrate this concept. They highlight the importance of understanding the mechanisms behind functional selectivity, including ligand-induced conformational changes, diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. The article also explores the potential impact of functional selectivity on drug discovery and the need to revise classic concepts in quantitative pharmacology. The authors suggest that functional selectivity may lead to the development of novel ligands that optimize therapeutic action by differentially activating specific functions of a receptor.The article discusses the concept of functional selectivity in pharmacology, challenging the traditional definition of intrinsic efficacy. Recent data have shown that ligands can differentially activate signaling pathways mediated by a single G protein-coupled receptor (GPCR), leading to phenomena such as agonist-directed trafficking and biased agonism. The authors present examples from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems to illustrate this concept. They highlight the importance of understanding the mechanisms behind functional selectivity, including ligand-induced conformational changes, diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. The article also explores the potential impact of functional selectivity on drug discovery and the need to revise classic concepts in quantitative pharmacology. The authors suggest that functional selectivity may lead to the development of novel ligands that optimize therapeutic action by differentially activating specific functions of a receptor.